Inactivation of viruses that may be present in a composition including a biological product that is intended for use in a biopharmaceutical product, such as a therapeutic drug or a vaccine, is an important aspect of quality control for ensuring that the biopharmaceutical product will work as intended and will not inadvertently cause disease or other harm. Viral contamination can occur during the production of a biological product, through both exogenous and endogenous sources. Viruses can be difficult to detect, given the diversity of their structures and genomes, and, once present, can be difficult to physically remove due to their small size. To account for the possibility of viral contamination, industrial processes for production of biological products typically include one or more steps for inactivation of potential viral contaminants.
Typical methods from the state of the art include adding a viral-inactivation reagent, such as an acid or a detergent, to a composition including a biological product, mixing thoroughly, incubating for a specific time, then neutralizing or removing the viral-inactivation reagent, all done in a discontinuous mode, i.e. batch mode, to accomplish inactivation of viruses that may be present in the composition including the biological product, as taught, for example by Ristol Debart et al., U.S. Pat. No. 6,875,848, Shadle et al., U.S. Pat. No. 5,429,746, and Latham et al, U.S. Pub. No. 2013/0236358. In accordance with such methods, inactivation of the viruses that may be present may require multiple discontinuous steps and/or extended incubation times, though, during which time the composition including the biological product typically is not otherwise processed, potentially adding substantial time to the overall process for manufacturing the biological product.
Other methods include treating a composition including a biological product with a dose of light, such as monochromatic or polychromatic light, in a continuous mode, e.g. as the composition flows through a thin-layer irradiator, optionally with mixing to narrow residence time distribution and increase inactivation rate, in order to accomplish inactivation of microorganisms that may be present in the composition, as taught, for example, by Anderle et al., U.S. Pat. No. 7,993,580. Control of the dose of light may be difficult, though, as the dose can vary across the composition depending on factors such as micro-heterogeneities in absorbance and rate of flow of the composition during irradiation, and can vary across time depending on aging of corresponding light sources and fluctuations in light emissions. Other methods include mixing a composition including a biological product with a viral-inactivation reagent, such as an acid or a detergent, continuously, e.g. using one or more in-line static mixers, during flow from a first unit operation to a second unit operation, in order to inactivate viruses that may be present in the composition, with residence time for virus inactivation being altered by having tubes of appropriate diameter and length after each static mixer and before a pH probe, as taught, for example, by Xenopoulos, WO2014/004103. Altering residence time for virus inactivation based on varying diameters and lengths of tubes after each static mixer and before a pH probe may require extensive empirical analysis and/or detrimentally long times of exposure of the biological product to the viral-inactivation reagent, though, given that patterns of flow of compositions in tubes may vary in ways that are complicated and difficult to predict, depending on specific properties of the compositions and dimensions of the tubes, and that patterns of flow of compositions in tubes can still exhibit heterogeneities notwithstanding thorough mixing of the compositions prior to flow of the compositions through the tubes, particularly in the context of scaling up a method for purposes of manufacturing.
Accordingly, a need exists for improved methods for continuously inactivating a virus during manufacture of a biological product, as well as for apparatuses providing treatment vessels specific for such methods.